Preparation of nu-acylamino-phenylpropane diols



United States Patent PREPARATEON OF N -ACYLA1\IIN O-PHENYL- PROPANEDIOLS No Drawing. Application June 25, 1954, Serial No. 439,472

Claims priority, application Germany June 38, 1953 9 Claims. (Cl.266558) The present invention relates to a process for the manufactureof amino-alcohols.

It is known to prepare amino-alcohols by reduction of the correspondingamino-acid esters with the aid of reducing agents customarily used forsuch reactions, for instance, complex metal hydrides, or by catalyticreduction. However, relatively poor yields are obtained by the knownprocesses since the recovery and isolation of the reducing agents iscomplicated and involves difficulties.

Now, We have found that amino-alcohols can be obtained in a pure stateand in good yield by reducing the corresponding N-acylated amino-acidazides with complex metal hydrides.

It is surprising that the process of this invention should afiordconsiderable advantage as compared with the direct reduction of theesters to the alcohols referred to above, for instance, with lithiumaluminum hydride, since, notwithstanding the intermediate stages forpreparing the azides from esters, the yields are better and the reactionproducts are obtained in a purer and more unitary state. In addition,the reduction products can be isolated much more easily than in theknown processes.

It could not be foreseen that the reduction of the azides to thecorresponding alcohols with elimination of the nitrogen would proceedsmoothly, especially as it is known that (a) By the reduction of thechlorides, nitriles or amides of fatty acids with lithium aluminumhydride the corresponding aldehydes are obtained in a poor yield, and

(b) Carbonyl groups linked to a nitrogen atom are reduced to methylenegroups, the nitrogen atom remaining in the molecule.

Acid amides, for instance, are reduced in this manner to methylaminescontaining the corresponding substituents, and acid iactams are reducedto cyclic imino compounds (Arzneirnittelforschung, volume 4, page Asstarting materials for the process of this invention there come intoconsideration azides. of monobasic and also polybasic monoanddiamino-acids of the aliphatic aromatic and heterocyclic series. Theremay especially be mentioned: threo-N-acetyl-fi-phenyhserine azide,threo- N-acetyl-fl-(4-chlorophenyl)-serine azide,threo-N-acetylfl-phenyl-B-methoxy-tx-aminopropionic acid azide, threo- Nacetyl 8 (4 nitrophenyl) B methoxy a aminopropionic acid azide,N-acetyl-phenylalanine azide, N acetyl (4 nitro phenyl) alanine azide, Nbenzoyl-y-amino-butyric acid azide, threo-N-acetyl-fl-(4-phenyl-phenyl)-serine azide, N-acetyl-fi-(4-chlorophenyl) ,8aminopropionic acid azide, N acetyl fl (2 nitrophenyl) B aminopropionicacid azide, threo N acetyl B (4 methyl mercapto phenyl) serine azide,threo-Ndichloracetyl-,6-(4-methyl-mercapto-phenyl)-serine azide,erythro-N-acetyl-B-(4-methylmercapto-phenyD-sen'ne azide,erythro-N-dichloroacetyl 8-(4-methyl-mercapto-phenyl)-serine azide and'DIJ- threo B (paranitrophenyl) N dichloroacetyl serine azide.

In order to prepare the amino-acid azides, the corresponding acidhalides may be reacted with alkali azides. Furthermore, the amino-acidazides can be prepared in an advantageous manner from the correspondingamino-acid esters through the. hydrazide stage. The intermediateproducts formed need not be isolated in this case. As starting materialsthere are used with advantage the esters of the acylated amino acidswith aliphatic alcohols, such as methyl, ethyl, propyl, isopropyl, butylor amyl alcohol. Starting from the corresponding amino-acid esters, thereaction may also be carried out with araliphatic or aromatic alcoholsor phenols, from which the general applicability of the reaction will beunderstood. When these compounds contain, in addition to the aminogroup, other reactive groups such as the hydroxyl groups, the latter maybe protected by acylation. The conversion of the amino-acid esters intothe corresponding hydrazides is advantageously carried out in an inertsolvent, the hydrazine being advantageously used in the form of itshydrate. Since the hydrazides obtained are sparingly soluble andprecipitate from the reaction mixture, they may be converted into thecorresponding azides without further purification. The conversion of thehydrazides into the azides is carried out in known manner,advantageously while cooling well, with nitrous acid, the latter beingliberated from a salt thereof during the reaction.

In this case it is not necessary to isolate the azides for thesubsequent reduction. Thus, they can be directly subjected to thefurther treatment with the addition of an organic solvent. As suchsolvents there come into con sideration, for instance, open or cyclicothers such as diethyl ether, tetrahydrofurane or dioxane, as well asaliphatic acid esters, especially ethyl acetate or mixtures of ethylacetate and ether.

As reducing agents there are used complex metal hydrides, for instance,lithium aluminium hydride, magnesium aluminium hydride, sodium boronhydride, potassium boron hydride, lithium boron hydride or the like.They may be added in solid form or in the form of solutions. Of specialadvantage is the use of complex boron hydrides which are stable inwater, especially sodium boron hydride, which enables the reduction tobe carried out in aqueous solvents, for instance, in aqueous alcohols,and which is very stable at temperatures of about 0 C. and, above all,in the presence of alkali.

Upon working up the reduction mixtures the reaction products areobtained in a relatively pure state and genorally in a good yield, incontradistinction to the known process of direct reduction.

If necessary, these products can be recrystallized from solvents such aswater, ether, petroleum ether, cyclohexanone, chloroform or carbontetrachloride.

The following examples serve to illustrate the invention, but they arenot intended to limit it thereto; the parts are by weight unlessotherwise stated, and the relationship of parts by volume to parts byweight is the same as that of the litre to the kilogram:

EXAMPLE 1 Thre0-O:N-riiacetyl-1-phenyI-Z-amino-prapandiol- (1 :3)

To a solution of 12.4 parts of N-acetyl-phenyl-serine azide in 200 partsby volume of ethyl acetate is added in the course of 10 minutes at 14 C.to 8 C., while stirring, a solution of 2.2 parts of sodium boron hydride(of 98 per cent strength) in 40 parts by volume of methyl alcohol.Subsequently, the whole is stirred for 2 hours at room temperature.After having filtered oiT the precipitated inorganic salts with suction,the ethyl acetate solution is shaken twice with sodium carbonatesolution of 5 per cent strength, and then with 0.5 N-sulphuric acid.

After concentrating the ethyl acetate solution, a residue of 1.5 partsof threo-1-phenyl-2-acetyl-amino-propandiol- 1:3 remains as a syrupymass which, by heating it with acetic anhydride at about 70 C., isconverted into three- :N-diacetyl-1-phenyl-2-amino-propandiol-1 :3(yield: 1 .4 parts, melting point: 168 C.).

N-acetyl-phenyl-serine azide is prepared in the following manner: 7

96 parts of threo-N-acetyl-phenyl-serine ethyl ester are converted inmethanolic solution with 40 parts of hydrazine hydrate into thecorresponding hydrazide (melting at 220 C.), and the latter is thenconverted by means of 29 parts of sodium nitrite in solution inhydrochloric acid intothe N-acetyl-phenyl-serine azide (yield: 68 parts;melting point: 140 C. with decomposition).

EXAMPLE 2.

T hreo-N -acetyl-1 -(4-ch lonophenyl -2-amin0-pr0pandiol- 7.28 parts ofthreo-N-acetyl-B-(4-chlorophenyl)-serine azide are suspended in 150parts by volume of ethyl acetate and cooled to 50 C. While stirring, asolution of 2 parts of sodium boron hydride (of 89 per cent strength) in20 parts by volume of methyl alcohol is then added in portions such thatthe temperature does not exceed 25 C. The reaction mixture is thenstirred for a further 30 minutes. The inorganic salts are filtered offwith suction, the filtrate is evaporated, and the residue remaining inthe form of a yellowish mass is recrystallised from hot water. 3 partsof threo-N-acetyl-l-(4-chlorophenyl)- 2-amino-propandiol-1:3 areobtained (melting at 164 C.l 65 C.).

The azide is prepared in the following manner:

32 parts of threo-N-acetyl-fi-(4-chlorophenyl)-serine ethyl ester(melting at 180 C.) are converted with 8 parts of hydrazine hydrate inethanolic solution into the corresponding hydrazide (yield: 27 parts,melting point: 256 C.), which is then converted with 2.5 parts of sodiumnitrite in solution in hydrochloric acid into the corresponding azide.

EXAMPLE. 3

Threo N benzoyl 1 phenyl 1 methoxy 2 aminopropanol-(3) 20.2 parts ofN-acetyl-fi-phenyl-18-methoxy-a-aminopropionic acid azide are taken upin 200 parts by volume of ethyl acetate and cooled to 45 C. Within 15minutes a solution of 2.9 parts of sodium boron hydride (of 89 per centstrength) in 40 parts by volume of ethyl alcohol is added whilestirring. After allowing the whole to stand for 2 /2 hours, theprecipitated inorganic salts are filtered off, and the residue, whichremains after evaporation of the ethyl acetate, in the form of alight-colored syrup is hydrolyzed by heating it for 4 hours under refluxwith 100 parts by volume of ZN-hydrochloric acid to yield the free amineor its hydrochloride. After being shaken with methylene chloride, thehydrochloric solution is evaporated to dryness. After the addition of anexcess of sodium hydroxide solution, the residue is benzoylated with 15parts by volume of benzoyl chloride. 5.6 parts ofthreo-N-benzoyl-l-phenyl-l-methoxy-Z-aminopropanol-(3) (melting at 164C.) are obtained.

The azide is prepared in the following manner:

10 parts of threo-N-acetyl-fi-phenyl-fi-methoxy-a-aminopropionic acidethyl ester (melting point 106 C.) are converted with 4 parts by volumeof hydrazine hydrate of 85 per cent strength in ethanolic solution intothe'corresponding hydrazide (yield: 5 parts, melting point: 232 C.). Byslowly adding 6 parts of sodium nitrite in satu- EXAMPLE 4 rated aqueoussolution, the hydrazide is converted in sul- I Threo N acetyl 1 (4nitrophenyl) 1 methoxy 2- amin0-propanol-(3 26 parts ofN-acetyl-B-(4-nitrophenyl)-B-methoxy-uamino-propionic acid azide aretaken up in 125 parts by volume of ethyl acetate. After treatment withsodium tetraborate, the solution is cooled to -30 C. to 45 C. Whilestirring and further cooling, a solution of 2 parts of sodium boronhydride (of 89 per cent strength) in 20 parts by volume of methylalcohol is added dropwise, and the whole is then stirred without furthercooling, until room temperature is reached. The precipitated inorganicsalts and the reaction product are filtered off with suction, the latteris extracted with acetonitrile and united with the quantity which wasobtained from the ethyl acetate mother liquor. After recrystallizationfrom acetonitrile diluted with water, there are obtained 2.6 parts ofthree- N acetyl 1 (4 nitro phenyl) 1 methoxy 2- amino-propanol-(3)melting at 2162l7 C.

The azide is prepared in the following manner:

2 parts of th'reo-N-acetyl-B-(4-nitrophenyl)-[3-methoxya-amino-propionicacid methyl ester (melting from 105 C. upwards) are suspended methylalcohol, then converted with 1.5 parts by volume of hydrazine hydrate of85 per cent strength into the corresponding hydrazide (melting at 248C.), and, by addition of an aqueous solution of 2.7 parts of sodiumnitrite, the hydrazide is converted in hydrochloric acid solution intothe corresponding azide.

EXAMPLE 5 N acetyl 1 phenyl 2 amino 3 aceloxy propane 6.3 parts ofN-acetyl-phenyl-alanine azide are taken up, While stirring, with partsby volume of ethyl acetate and, after treatment with sodium tetraborate,the solution is cooled to 40 C. While further cooling, a solution of 1.8parts of sodium boron hydride (of 89 per cent strength) in 20 parts byvolume of methyl alcohol is added in small portions. The solution isthen stirred, without cooling, until room temperature is reached and isseparated from the precipitated inorganic salts by filtering withsuction.

After eliminating the solvent, the oily residue is heated with 10 partsby volume of acetic anhydride for 1 hour on the steam bath. The excessof acetic anhydride is distilled oif, the residue is taken up in ethlyacetate and, after evaporation of the solvent,N-acetyl-l-phenyl-Z-amino- 3-acetoxy-propane is recrystallized frompetroleum ether (yield 3.1 parts, melting point 117 C.).

The azide is prepared in the following manner:

6 parts of N-acetyl-phenyl-alanine hydrazide are converted with anaqueous solution of 2.5 parts of sodium nitrite into the correspondingazide which separates in the form of flakes.

EXAMPLE 6 N -acetyl-l (4-nitrophenyl -2-amin0-3 -acet0xy-pr0pane 8.33parts of N-acetyl-(4-nitrophenyl)-alanine azide are taken up in 270parts by volume of ethyl acetate and treated with a sodium tetraboratesolution.

The solution is cooled to 40 C. and, while stirring and further cooling,a solution of 1.8 parts of sodium boron hydride (of 89 per centstrength) in 20 parts by volume of methyl alcohol is slowly added. After10 minutes, when the mixture has reached room temperature, it isseparated from the precipitated inorganic salts by filtration withsuction. The filtrate is then evaporated.

The partly crystalline mass is heated with 30 parts by volume of aceticanhydride for 1 hour on the steam bath, the mixture is then filtered,and the excess of acetic anhydride is distilled off. The residue,consisting of N-acetyl- 1(4-nitrophenyl) -2-amino-3-acetoxy-propane, isrecrystallized from aqueous methyl alcohol (yield: 3.7 parts, meltingpoint: 162 C.).

The azide is prepared in the following manner:

14.4 parts of N acetyl N (4 -nitrophenyl) alanine methyl ester areconverted with 5 parts by volume of hydrazine hydrate of 85 per centstrength in ethanohc solution into the corresponding hydrazide (yield:11.4 parts, melting point 215 C.). By the addition of an aqueoussolution of 2.5 parts of sodium nitrite, the hydrazide is converted inhydrochloric acid solution into the corresponding azide.

EXAMPLE 7 N-benzyl-4-aminobutanol-(1 50.4 parts ofN-benzoyl-v-amino-butyric acid azide are taken up in 60 parts by volumeof ethyl acetate and, after a treatment with sodium tetraboratesolution, a solution of 1.5 parts of sodium boron hydride in 15 parts byvolume of methyl alcohol is added dropwise, while stirring well at 45 C.After removal of the cooling device and when the solution has reachedroom temperature, the precipitated inorganic salts are filtered oil?with suction and the solvent is distilled off. The residue it taken upin chloroform, the solution is filtered and, subsequently, thechloroform is distilled off. The residue, which is a lightcolored oil,very soon crystallizes. The crystals are filtered off with suction andwashed with ether. After recrystallization from chloroform andcyclohexane there are obtained 2.2 parts ofN-benzoyl-4-amino-butanol-(1) (melting at 78 C.).

The azide is prepared in the following manner:

10 parts of N-benzoyl-y-amino-butyric acid methyl ester are convertedwith 25 parts by volume of hydrazine hydrate of 25 per cent strengthinto the corresponding hydrazide (yield: 4.8 parts, melting point: 119C.). By the addition of an aqueous solution of 1.8 parts of sodiumnitrite, and while cooling and stirring, the hydrazide is converted inhydrochloric acid solution into the corresponding azide.

EXAMPLE 8 Threo-N-acetyl-J-(4-phenyl-phenyl) -2-amin0- propanol- (3) 6.4parts of N-acetyl-B-(4-phenyl-phenyl)-serine azide are suspended, whilestirring, in 60 parts by volume of ethyl acetate and, while cooling wellto -40 C., a solution of 2 parts of sodium boron hydride in 20 parts byvolume of methyl alcohol is added. The reaction sets in suddenly whilethe temperature rises to |-5 C.

The inorganic salts are filtered oif after one hour and the ethylacetate is evaporated. The oily residue is dissolved in hot chloroform,the solution is filtered and concentrated. Thereupon petroleum other isadded and the precipitate formed is filtered off with suction. After atreatment with a sodium carbonate solution of per cent strength, theprecipitate is again filtered off with suction and subsequently washedwith water. By recrystallization from aqueous methyl alcohol there areobtained 3.3 parts ofthreo-N-acetyl-1-(4-phenyl-phenyl)-2-aminopropanol-( 3) (melting at194l95 C.).

The azide is prepared in the following manner:

184 parts of threo-fi-(4-phenyl-phenyl) -serine (melting at l84-187 C.),obtained by reaction of 4-phenylbenzaldehyde with amino-acetic acid, areconverted in the usual manner into the 4-phenyl-phenyl-serine methylester (melting point 114 C.). The threo-N-acetyl-(4-phenyl-phenyl)-serine methyl ester (melting point: 214 C.) obtainedtherefrom by acetylation with acetic anhydride is converted into thecorresponding hydrazide (melting at 2l6-219 C.) with a mixture of 25parts by volume of hydrazine hydrate of 85 per cent strength and 300parts by volume of dioxane. The hydrazide is then dissolved indimethyl-formamide and, with the addition of hydrochloric acid, isconverted into the corresponding azide with an aqueous solution of 2.5parts of sodium nitrite.

off with suction.

6 EXAMPLE 9 O:N-diacetyl-1- (4-chlor0ph enyl) -amin0-pr0panol- (3) Asolution of 9.18 parts of N-acetyl-fi-(4-chlorophenyl)-fl-amiuo'propionic acid azide in 115 parts by volume of ethyl acetateis wished with a small quantity of sodium tetraborate solution, and isthen filtered. A solution of 2 parts of sodium boron hydride (of 96 percent strength) in 20 parts by volume of methanol is .added dropwise at40 C. After cessation of the reaction, the whole is stirred for afurther hour at room temperature. The inorganic salts formed arefiltered off and the ethyl acetate is evaporated. The residue isdissolved in chloroform, the solution is filtered and the solvent isevaporated.

The product is acetylated in the usual manner with acetic anhydride. Theresidue remaining after evaporation of the excess of acetic anhydride isrecrystallized from benzene, petroleum ether, and O':N-diacetyl-1-(4-ehlorophenyl)-1-amino-propanol-(3) is obtained (yield: 5.5 parts,melting point: 114 Q).

The azide is obtained in the following manner: 7

19 parts of N-acetyl-B-(4-chlorophenyl)-,B-amino propionic acid methylester (melting point: 119 C.) are converted in methanolic solution intothe corresponding hydrazide (melting at 228 C.) by means of 12 parts byvolume of hydrazine hydrate of 85 per cent strength. While cooling, thehydrazide is then converted in hydrochloric acid solution into thecorresponding azide with an aqueous solution of 3.3 parts of sodiumnitrite.

EXAMPLE 10 O.'N-rliacetyl-1- (2-nitr0phenyl) -1-amin0-pr0pan0l- (3) 4.4parts of N-acetyl-fl-(2-nitrophenyl)-,B-amino-propionic acid azide aresuspended in parts by volume of ethyl acetate. While stirring, there isadded dropwise at -25 C. a solution of 1.5 parts of sodium boron hydridein 15 parts by volume of methyl alcohol. After 30 minutes thetemperature is allowed to rise to room temperature, and the inorganicsalts formed are filtered After evaporation of the solvent, the residueis extracted with chloroform, the solution is filtered, and the solventis evaporated.

The remaining syrup is heated for 1 hour on the steam bath with 10 partsby volume of acetic anhydride and the excess of acetic anhydride isevaporated under reduced pressure. The crystalline residue is filteredoff with suction and washed with ether. By recrystallization frombenzene there are obtained 1.6 parts ofOzN-diacetyl-1-(2-nitropheny1)-l-aminopropanol-(3) (melting at 106 C.).

The azide is prepared in the following manner:

12 parts of N-acetyl-fi-(2-nitrophenyl)- 3-amino-propionic acid methylester (melting at 156 C.) are converted in methanolic solution into thecorresponding :hydrazide (melting at 212 C.) by means of 5 parts byvolume of hydrazine hydrate of per cent strength. In hydrochloric acidsolution the hydrazide is then converted into the corresponding azidewith an aqueous solution of 2 parts of sodium nitrite.

EXAMPLE 11 DL-th reo-I para-nitrophenyl -2- (N -dich loracetylamino)-pr0pandi0l- 1 :3)

A solution of 35 parts of sodium boron hydride in 375 parts by volume ofmethanol is added within 30 minutes, while stirring and cooling to 35C., to 321 parts of DL-threo-B-(paranitrophenyl)-N-dichloracetylserineazide in a mixture of ether and ethyl acetate. The whole is then stirredfor a further hour. Subsequently, the inorganic salts are filtered offwith suction and washed with ethyl acetate. The combined ethylacetate-ether solutions are washed with 0.5N-sulphuric acid, and thenwith sodium bicarbonate solution and water. By evaporation of thesolvent, there are obtained 298 parts of the crudeDL-threo-l-(para-nitrophenyl)-2- EXAMPLE 12 DL-threo-Z para-mi trophenyl-2- (N -dichloracetylamino) -prpandi0l- (1 :3)

20 .parts of DL-threo-B- (para-nitrophenyl)-N-dichloracetyl-serine azideare dissolved in anhydrous ether and, while stirring and cooling well, asolution of 4 parts of lithium aluminium hydride in 500 parts by volumeof anhydrous ether is added dropwise. After further stirring for 2hours, 20 parts by volume of water are added to the reaction mixture.Then the residue is separated from the ether .by filtering with suction,and extracted under reflux 3 times for 30 minutes on each occasion withboiling ethyl acetate. The combined ethyl acetate extracts are shakenwith lN-hydrochloric acid or lN-sulphuric acid, then with 0.5N-sodiumcarbonate solution, and finally washed with water until neutral. Theresin remaining after concentration of the ethyl acetate solution istaken up in boiling water. The solution is then treated, while hot, withactive charcoal, concentrated under reduced pressure to half its volume,and clarified once more with active charcoal.

After further concentration to 50 parts by volume, DL-threo-l-(para-nitrophenyl)-2 (N dichloracetylamino)- propandiol-(lfi)(melting at 152C.) crystallizes out.

The azide is prepared in the manner described in Example 11.

We claim:

1. The process of preparing acylamino-alcohols, which comprises reactingan amino-acid azide having the formula wherein R is a member selectedfrom the group consisting of N-lower alkanoyl, N-(halo-lower alkanoyl)and N-benzoyl radicals, wherein R is a member selected from the groupconsisting of hydroxy, lower-alkoxy and acetoxy radicals, and wherein R2is a member selected from the group consisting of hydrogen, chloro,nitro, methylmercapto, and phenyl radicals, with a member selected fromthe group of complex metal hydrides consisting of alkali metal boronhydrides, alkali metal aluminum hydrides, alkaline earth metal boronhydrides and alkaline earth metal aluminum hydrides, in the presence ofan aliphatic oxygen-containing solvent to thereby form an intermediatecomplex and'in the presence of a member selected from the groupconsisting of water and a lower aliphatic alcohol as hydrogen donatorsfor breaking up the intermediate complex, and adding water to thereaction mixture thus obtained to thereby obtain the correspondingacylamino alcohol in a pure state.

2. The process of claim 1, wherein said azide has the formula OH O Rrepresenting an N-loweralkanoyl radical.

3. The process of claim 1, wherein said azide has the formula OH O Rrepresenting an N-(halo-lower alkanoyl) radical.

4. The process of claim 1, wherein said azide has the OH O Rrepresenting an N-benzoyl radical.

5. The process of claim 1, wherein said azide isthreol-(para-nitrophenyl) -2-N-dichloracetylserino azide.

6. The'process of claim 1, wherein said oxygen-containing solvent is anaqueous lower aliphatic alcohol and said complex metal hydride is analkali metal boron hydride.

7. The process of claim 1, wherein said azide has the OH 0 Rrepresenting an N-(halo-lower alkanoyl) radical, said oxygen-containingsolvent is aqueous methyl alcohol, and said complex metal hydride issodium boron hydride.

8. The process of claim 1, wherein said azide has the formula H I O Rrepresenting an N-(halo-lower alkanoyl) radical, and said complex metalhydride is an alkali metal aluminum hydride.

9. The process of claim 1, wherein said azide has the formula Rrepresenting an N-(halo-lower alkanoyl) radical, and said complex metalhydride is lithium aluminum hydride.

References Cited in the file of this patent Boyer: J. Am. Chem. Soc.,vol. 73 (1951), pp. 5865-66.

1. THE PROCESS OF PREPARING ACYLAMINO-ALCOHOLS, WHICH COMPRISES REACTINGAN AMINO-ACID AZIDE HAVING THE FORMULA
 4. THE PROCESS OF CLAIM 1,WHEREIN SAID AZIDE HAS THE FORMULA